1. Field of the Invention
The present invention relates to monitoring and/or controlling dehydration of products during a vacuum-drying process and more particularly to detecting the end of sublimation of water contained in products subjected to freeze-drying.
2. Description of the Prior Art
Freeze-drying is a low-temperature process that eliminates by sublimation most of the water contained in a product. The industries to which this process is most relevant are the foodstuffs industry, the pharmaceuticals industry (vaccine, serum, medication) and the bio-industries (yeast), the process assuring long-term conservation of an active principle (exhibiting biological and/or medication activity) in a product that will be stored at a temperature close to room temperature.
Monitoring dehydration kinetics during freeze-drying is essential for controlling manufacturing costs and additionally for obtaining a freeze-dried product of good quality. The stability of a product stored under these conditions is extremely sensitive to very small variations in the amount of residual water that it contains. Although it reduces costs, a cycle that is too short yields a product that is too moist. Fast deterioration of the quality of the product is then generally observed. Conversely, an operating cycle that is too long may cause the product to deteriorate through overheating, as well as incurring additional costs with no benefit. Increasing the temperature too early on in the process may lead to fusion or partial fusion of the product, resulting in a defective appearance. This fabrication accident is usually accompanied by significant or even unacceptable degrading of certain of the properties of use required in the end product (purity, suitability for rehydration). Reliable monitoring of the dehydration of such products therefore proves to be essential.
The freeze-drying process comprises two successive operations: freezing and dehydration. The dehydration operation comprises two steps, corresponding to two different physical phenomena: sublimation of ice crystals that are formed during freezing, often referred to as “primary desiccation”, and final desorption of water that is not frozen, often referred to as “secondary desiccation”. Sublimation is usually achieved by input of heat and reducing the total pressure (vacuum freeze-drying). The problem is to determine the passage from one step to another and the end of the operation as accurately as possible.
The freezing operation is generally conducted at atmospheric pressure. The dehydration operation necessitates reducing the water vapor pressure below the triple point, after which the passage of the water to the vapor state is encouraged by a pressure reduction. Throughout the sublimation step, and for as long as the product contains ice, the temperature of the product will remain identical to the temperature at which it was frozen. When the product contains no more ice, i.e. at the end of primary desiccation, the temperature of the product rises.
The method of monitoring freeze-drying that is most widely used in an industrial environment measures how the temperature of the product evolves during treatment. In particular, this enables the end of primary desiccation to be determined. Temperature probes are placed in the heart of the product before freezing and the evolution of the temperature signal is then recorded during freeze-drying. As long as the probe remains in the frozen heart of the product, the measured temperature evolves very slowly. On the other hand, as soon as the probe is no longer in contact with ice, the measured temperature changes very quickly, which reflects the accumulation of heat in the dry layer. Freeze-drying is stopped (or the set point is changed to begin the secondary desiccation step) when all the temperature probes at different locations in the processing enclosure indicate the same value. Products placed in the same enclosure can exhibit different rates of desiccation, and a difference of several hours in the time to reach the reference temperature may be observed between the various probes. The safety measure that consists in waiting several hours for all the temperature values to be the same before stopping the cycle imposes an additional process cost, which is sometimes high, and reduces efficiency. Moreover, the number of probes used is generally small (of the order of four or five probes for 150 000 products to be freeze-dried), which can lead to a rejection rate of up to 10% for a batch of product.
Other measuring systems have been envisaged for monitoring vacuum freeze-drying kinetics, for example by measuring the electrical resistance or the dielectric constant of the product during treatment. The passage of the front at the electrodes placed in the product varies these magnitudes. Furthermore, the dielectric constant of liquid water being very much higher than that of ice, it is possible to detect melting phenomena.
The major drawback of the above indirect methods is their localized character and lack of sensitivity. The temperature curves are insufficiently accurate and do not enable the exact end of primary desiccation to be determined, for example.
A control method was therefore envisaged that takes account of the whole system. In particular, it was proposed to use a method of monitoring process kinetics based on thermal balances for the heating plates and the ice trap of the freeze-drier. Monitoring the liquid nitrogen consumption of the cold trap enables a thermal balance to be drawn up. In theory this method gives the intensity of the transfer of heat at all times, and consequently the quantity of water vapor produced. However, the quality of the thermal balance is adversely affected by the accuracy of the temperature probes and by thermal losses, which are difficult to quantify.
Measuring the mass of the trays containing the product or of the condenser is one way to monitor water loss kinetics during treatment. The tray-support system or the cold trap fixed to a frame are equipped with strain gages whose deformation can be correlated to the quantity of water extracted from the product and trapped in the form of ice. Unfortunately, this apparently reliable method cannot be easily adapted to most freeze-drying equipment already installed, and its cost remains high. A materials balance for the water vapor given off in the enclosure can equally be obtained by direct measurement using a water vapor pressure sensor. There remains the problem of the accuracy of the measurement at the end of the process for all these methods.
If the condenser is outside the freeze-drying enclosure, it is possible to monitor the evolution of the total pressure in the freeze-drying enclosure after closing a valve connecting the enclosure to the trap (this is called the barometric method). Ignoring air leaks, any fast rise in pressure indicates a high rate of sublimation and reflects the presence of residual ice. The resolution of the method (impact of pressure rise on freeze-drying kinetics) and its accuracy at the end of the cycle (when little water vapor is given off) define its limits.
More recently, a method based on mass spectrometer measurement has been envisaged that analyzes materials balances throughout the freeze-drying enclosure. This method produces the most accurate and the most uniform measurements, leading to true monitoring of dehydration. Unfortunately, in some aseptic process industries, such as the pharmaceuticals industry, sterilization of the measuring equipment is required. The mass spectrometer is not able to withstand sterilization stresses and therefore cannot be sterilized. To solve this problem, a valve fitted with a filter is inserted between the mass spectrometer and the enclosure. This method has certain limitations, however, resulting in particular from clogging of the filters. There is a risk of contamination of the freeze-drying enclosure via the filter. Moreover, the use of a mass spectrometer is costly because it necessitates the use of a secondary pump and the frequent renewal of consumable components like the filament.
Like the method using a mass spectrometer, the other methods proposed also give rise to problems if sterilization proves necessary.
An object of the present invention is therefore to propose a device and a method for controlling dehydration during freeze-drying that does not have the drawbacks of the prior art methods cited above. In particular, the invention proposes a device and a method for determining accurately the end of the primary desiccation step. The invention also proposes a device and a method that are compatible with strict requirements in terms of aseptic conditions, and in particular that avoid recourse to sterilization.